Preparation of amino-ethyl isoxazolyl substituted tetrahydropyrans and intermediates therefor

ABSTRACT

Alternate process routes to 2-(substituted amino)-6-(2-(3,5dimethyl-4-isoxazolyl)ethyl)-tetrahydropyran-2-ols and their optionally alkylated analogs are described. The preparative routes involve multi-step procedures starting from 2-(2&#39;&#39;substituted aminoethyl)-2-hydroxy-6-vinyl-tetrahydropyrans and their alkyl substituted analogs including a last step isomerization and amine addition to a 1-(3,5-disubstituted-4isoxazolyl)-7-hydroxy-non-8-en-3-one or its tautomer. The final product aminoethyl-isoxazolyl substituted tetrahydropyrans are intermediates useful in the preparation of pharmaceutically valuable steroidal compounds. In preferred embodiments the amino substituent group in the final products is an optically active amine which renders such products particularly suitable, via resolution procedures, to serve as intermediates in the preparation of optically active steroidal compounds.

United States Patent Saucy 51 June 20, 1972 [54] PREPARATION OFAMINO-ETHYL ISOXAZOLYL SUBSTITUTED TETRAHYDROPYRANS AND INTERMEDIATESTHEREFOR [72] Inventor: Gabriel Saucy, Essex Fells, NJ.

[73] Assignee: Hoffman-La Roche Inc., Nutley, NJ.

[22] Filed: Jan. 19, 1970 [21 Appl. No.: 4,026

[52] U.S. Cl ..260/307 H, 260/2475 R, 260/293.67. 260/345.9, 260/566 A[5 i Int. Cl. ..C07d 85/22 [58] Field of Search ..260/307 H, 345.9,247.5 R, 260/293.67

[56] References Cited UNITED STATES PATENTS 3,553,228 l/l97l Freedman..260/307 Primary Examiner-Alex Mazel Assistant Examiner-R. V. RushAttorney-Samuel L. Welt, Jon S. Saxe, Bernard S. Leon, William H.Epstein and George M. Gould [5 7] ABSTRACT Alternate process routes to2(substituted amino)-6-( 2-[3,5-dimethyl-4-isoxazolyl]ethyl)tetrahydropyran-2-ols and their optionallyalkylated analogs are described. The preparative routes involvemulti-step procedures starting from 2-(2'-sub stitutedaminoethyl)-2-hydroxy-6-vinyl-tetrahydropyrans and their alkylsubstituted analogs including a last step isomerization and amineaddition to al-(3,5-disubstituted-4-isoxazolyl)-7-hydroxy-non-8-en-3-one or itstautomer. The final product aminoethyl-isoxazolyl substitutedtetrahydropyrans are intermediates useful in the preparation ofpharmaceutically valuable steroidal compounds. In preferred embodimentsthe amino substituent group in the final products is an optically activeamine which renders such products particularly suitable, via resolutionprocedures, to serve as intermediates in the preparation of opticallyactive steroidal compounds.

12 Claims, No Drawings PREPARATION OF AMINO-ETHYL ISQXAZOLYL SUBSTITUTEDTETRAHYDROPYRANS AND 'INTERMEDIATES THEREFOR BRIEF DESCRlPTlON OF THEINVENTION The present invention relates to novel processes useful in thepreparation of compounds of the following fon'nula R ll ll where R R andR are selected from the group consisting of hydrogen and lower alkyl; Ris selected from the group consisting of hydrogen, lower alkyl, loweralkylaryl and aralkyl; R taken independently is hydrogen or lower alkyl;R, taken independently is lower alkyl or aralkyl; and R, and R takentogether with the adjacent nitrogen atom form a 5 or 6 memberedsaturated heterocyclic ring including at the most one additional heteroatom selected from the group consisting of nitrogen and oxygen.

As used herein the term lower alkyl is meant to include both branchedand straight chain hydrocarbon radicals having from one to seven,preferably one to four carbon atoms. Ex

amples of suitable lower alkyl groups include methyl, ethyl,

propyl and butyl. Examples of suitable lower alkyl aryl groups includetolyl, xylyl and the like. The term aralkyl" is meant to include groupssuch as phenyl-lower alkyl, e.g., benzyl and phenylethyl.

The processes of the present invention utilized in the preparation ofcompounds of formula 1 above are more readily understood by reference tothe following reaction scheme:

REACTION SCHEME i l L 0 OH J III HO NHzOH IIb H -R| I I 0 R3 1 N\ A I inO R: O V

lei

where R R R R R, and R are as above; and R and R, are defined as R; andR respectively both independently and when taken together.

In step (a) of the process of the present invention compounds offormulas Ila or llb are reacted with a diketone compound of thefollowing formula O O VII where R, and R are as above.

The reaction sequence outlined in the above reaction scheme utilizeseither vinyl ketones of the structure shown in Formula lla or aminoketones of Formula llb as alternative starting materials. It is to benoted that when the amino ketones of Formula llb are placed in solutionsome of this compound is converted to the vinyl ketone of Formula lla.

-Either type of compound or mixtures thereof can be used as startingmaterial. The amino moiety represented by R,R N in formula llb can be alower alkyl amine such as methylamine, ethylamine, propylamine,n-butylamine, hexylamine, etc., preferably n-butylamine; aralkylaminessuch as Ia-methylbenzylamine or amines of complex molecules such as, forexample, dehydroabietylamine. Suitable amino groups also includedi-lower alkylamines which may optionally contain additionalsubstituents on the alkyl group, e.g., phenyl or cyclic amino groups.Examples of such di-substituted amines include dimethylamine,diethylamine, methylethylamine and the like. Diethylamine is preferred,The amino moiety may also comprise a cyclic group optionally containingan additional hetero atom in the ring. Examples of cyclic amines includepyrrolidine and piperidine. Morpholine is an example of a cyclic aminehaving an additional hetero atom.

' The preparation of starting materials of Formula II is described inus. Patent application Ser. No. 834,547, filed June 18, 1969, inventorGabriel Saucy, and also in Ser. No. 830,491, filed June 4, 1969,inventor Gabriel Saucy.

This reaction is conveniently conducted at a temperature in Q the rangeof from about 20 to 200 C., most preferably at the reflux temperature ofa suitably high boiling inert organic sol- :vent. Suitable inert organicsolvents for this purpose include 'the aromatic hydrocarbons, mostpreferably xylene" or toluene. The reaction product obtained isacompound of Formula lll which as indicated in the above Reaction Schemeis believed to exist as an equilibrium mixture of the two structuresshown. Infrared and nuclear magnetic resonance spectra indicate that apredominant form in this equilibrium is the enol form. However, it isunderstood that this equilibrium can be shifted by changes in theambient conditions such as temperature, selection of solvent system, andthe pH of the solu- .,tion. The exact structure of compounds of Formulalll is not believed to be critical to the practice of the presentinvention since both of the indicated forms are useful in furthertransformations. It is also possible to use compounds of Formula 11] incrude form for such further transformations. I

Compounds-of Formula III are then treated with hydroxylamine or a saltthereof in step (b) to yield mixed isomers of the bisoxime of FormulaIV. This reaction is conveniently conducted at a temperature in therange of from about .20 to 100 ,C.,'most preferably at about roomtemperature. Suitable salts of hydroxylamine include the mineral acidsalts of hydroxylar'nine, most preferably the hydrochloride salt. Thisreaction is most desirably conducted in the presence of an organic base,most preferably a tertiary amine such as a trilower alkylamine, e.g.,triethylamine.

In step (c), the above bis-oxime of Formula IV is converted by heatingto the isoxazole oxime of formula V. Suitable solvents for use in thistransformation step include organic solvents having a boiling pointabove about 50200 C., and include, for example, aromatic hydrocarbonssuch as toluene and xylene. Generally, the reaction is most desirablyconducted at the reflux temperature of the solvent medium. Compounds ofFormula V need not be purified prior to undergoing the next process stepin the reaction scheme.

In step (cl) compounds of Formula V are subjected to aqueous acidhydrolysis to yield compounds of Formula VI. It is understood thatcompounds of Formula VI may exist as an equilibrium tautomeric mixtureof the indicated tetrahydropyranol form and the corresponding openhydroxy ketone compounds. Particularly suitable aqueous acids for use inthe above hydrolysis step include the mineral acids, e.g., sulfuricacid, hydrochloric acid, phosphoric-acid and the like. A most preferredaqueous acid for this purpose is dilute sulfuric acid, e.g., 1N sulfuricacid. The hydrolysis reaction may conveniently be conducted at atemperature in the range of from about to 100 C., most preferably atabout room temperature. The reaction may also be conducted in thepresence of an added inert organic solvent. Suitable solvents-for thispurpose include ketones such as acetone and methyl ethyl ketone. Acetoneis the solvent of preference for this purpose.

In the final reaction step, step (e), compounds of Formula VI areconverted to compounds of Formula I by treatment of the former compoundswith a reaction medium comprising a metal alkoxide and an organic amine.Suitable metal alkoxides useful in the practice of this reaction stepinclude the aluminum lower alkoxides and sodium lower alkoxides, e.g.,aluminum isopropoxide and sodium methoxide. Aluminum isopropoxide is theagent of greatest preference in this reaction step.

The amine compound may be represented by the formula R RgNH; Examples ofsuitable amines include the lower alkylamines such as methylamine,ethylamine, propylamine, nbutylamine, hexylamine, me, most preferablyn-butylamine; alkylamines such as a-methylbenzylamine or amines ofcomplex molecules such as, for example, dehydroabietylamine. Suitableamines also include the di-lower alkylamines which may optionallycontain additional substituents on the alkylgroup, e.g., phenyl orcyclic amino groups. Examples of such di-substituted amines includedimethylamine, diethylamine, methylethylamine and the likev Diethylamineis preferred. The amine compound may also comprise a cyclic groupoptionally containing an additional hetero atom in the ring. Examples ofcyclic amines include pyrrolidine and piperidine. Morpholineticallyactive compounds of Formula I which are eminently suitable asintermediates in the preparation of optically active steroids ofvaluable pharmacological properties.

Temperature conditions useful in the practice of reaction step (e)include a temperature in the range of from about 0 C. to the refluxtemperature of the reaction medium, most .preferably at about the refluxtemperature of the reaction medium. This reaction may conveniently beconducted in the presence of an inert organic solvent. Suitable solventsfor this H V n where R R R and R. are as above.

A by-product obtained from the process of step (e) is the isomericS-hydroxy compound of the formula:

Rl \O R3 where R,, R R R R and R are as above.

Compounds of Formula IX can be separated from the desired product ofFormula I by chromatography over alumina. The compounds of Formula IXcan be isomerized to give a mixture containing a major amount ofcompounds of Formula I by treatment of the former compounds with themetal alkoxideunder the conditions used in step (e The compounds of theformulas III, IV, V and VI above are novel intermediates and as suchform a part of the present invention. Preferred embodiments of theprocess and compound aspects of the present invention are obtained whenR and R .both are hydrogen, R and R both are lower alkyl, R is hydrogenor lower alkyl, most preferably ethyl, R is lower alkyl, most preferablyethyl or aralkyl, most preferably phenethyl, and R and R both are loweralkyl, most preferably ethyl.

Starting materials of Formula II may be prepared in accordance withprocedures described in detail in U. S. Patent application Ser. No.818,142, filed Apr. 21, 1969, title, Preparation of TricyclicIntermediates, inventors, David Andrews and Gabriel Saucy.

The conversion of compounds of Formula I into racemic or opticallyactive l9-norsteroids of known pharmacological value is described indetail in U. S. Patent application Ser. No. 778,314, filed Nov. 22,1968, inventors Gabriel Saucy and John William Scott.

The present invention will be more clearly understood by reference tothe following examples.

I EXAMPLE I Preparation of 2-hydroxy-2-( 3-acetyl-4-oxopentyl)-6-vinyltetrahydropyran Into a 500 ml. flask equipped with condenser,thermometer, nitrogen inlet and magnetic stirrer were placed 45.4 g. of2-[2 -diethylaminoethyl]-2-hydroxy-6-vinyltetrahydropyran, 40.0 g. of2,4-pentanedione and 250 ml. of toluene. The mixture was degassed,placed under nitrogen and heated 3- /5 hours at reflux. At this point,20.0 g. of 2,4-pentanedione was added and heating at reflux wascontinued three more hours. The solution was then cooled, transferred toa round bottom flask and evaporated in vacuo (60 C., 15 mmHg) withagitation. The resulting oil was then placed under high vacuum at 50 C.agitation to ensure removal of the last traces of excess H a C, 66.11%

-H, 8.72%; C, 66.27% H, 8.63%.

EXAMPLE 2 Preparation of 3-acetyll O-hydroxy-Z,7-dihydroxyiminodocecvll-ene lnto a 2liter flask equipped with mechanical stirrer were placed63.2 g. of crude 2-hydroxy-2-'( 3'acety1-4-oxopentyl)-6-vinyltetrahydropyran, 450 ml. of absolute ethanol, 89 ml. oftriethylamine and 28.0 g. of hydroxylamine hydrochloride. A slighttemperature rise occurred when the hydrochloride was added. The slurrywas stirred at room temperature for 8 hours as the hydrochloridegradually dissolved. The resulting solution was evaporated to drynesswith agitation at 60 C. and mm Hg. Small portions of toluene were addedto the residue to remove the last traces of ethanol. The resulting pastymixture comprised the above-titled product and triethylaminehydrochloride and can be utilized in crude form in furthertransformations.

Found:

EXAMPLE 3 Preparation of 1-(3,5-dimethyl 4-isoxazolyl)-7-hydroxy-3-hydroxyimino-non-8-ene The crude mixture of the dioxime andtriethylamin hydrochloride obtained in Example 2 was combined with 700ml. of toluene and the mixture was degassed. It was then placed undernitrogen and heated at reflux for three hours. The resulting slurry wascooled, stirred with 500 ml. of water and the mixture was transferred toa separatory funnel with ether rinsing. The aqueous phase was separatedand extracted twice with ether. The combined ether extracts and toluenelayer were then extracted with 2 X 50 ml. and then 1 X 25 m1. ofClaisens alkali which is made by dissolving 70 g. of potassium hydroxidein 50 ml. of water, cooling, adding 200 ml. of methanol and coolingagain before use. The combined alkali extracts were washed with 3 X 50ml. of 1:1 ether/benzene mixture and the washings were discarded. Thewashed alkali solution was then combined with an equal volume ofmethylene chloride in an Erlenmeyer flask and neutralized by thedropwise addition of acetic acid with stirring and external cooling tomaintain the temperature at 25 C. or less. When pH 6 was obtained, themixture was transferred to a separatory funnel and 125 ml. of saturatedbrine was added. At the start of shaking, the organic layer wasseparated and the aqueous phase was extracted twice with 100 ml.portions of methylene chloride. The combined organic phase and methylenechloride extracts were washed with 100 ml. of 1:1 saturatedbrine/saturated sodium bicarbonate solutions, dried over anhydroussodium sulfate and vacuum evaporated at 60 C. and 15 mm Hg. withagitation to give 38.2 g. of l-(3,5-dimethyl-4-isoxazolyl)-7-hydroxy-3-hydroxyimino-non-8-ene as a brownviscous oil. A sample of this product was purified by columnchromatography and then analyzed. Based on the ir and nmr spectra, theoxime group is present in both its syn and anti form.

A total of 38.2 g. of crude l-(3,5-dimethyl-4-isoxazolyl)-7-hydroxy-3-hydroxyimino-non-S-ene was dissolved in 225 ml. of acetone and100 ml. of 1N sulfuric acid was added with stirring. The solution wasallowed to stand at room temperature for two days and was then vacuumevaporated at 35 C. and 15 mm Hg. to remove the organic solvent. Theresulting aqueous emulsion was partitioned between 250 ml. of water and200 ml. of methylene'chloride. The aqueous phase was extracted with 100ml. of methylene chloride and the combined organic extracts were washedwith 100 ml. of 1:1 saturated brine/saturated sodium bicarbonatesolution. The organic phase was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to give 31.8 g. of crude product as abrown oil. The product can be purified by passage through a chromatographic column packed with alumina (Activity 111) and using benzene aseluting solvent until first product appears and then eluting theremainder of the product from the column using a 9:1 benzene/ethermixture. A sample of this product was further purified by short-pathdistillation; b.p. 179 C. at 0.2 mm Hg.

C H NO Calcd.: C, 66.91%; H, 8.42%; N, 5.57% Found: C 66.88%; H, 8.40%;N, 5.32%

EXAMPLE 5 Preparation of 2-(diethylamino)-6-(2-[3,5-dimethyl-4-isoxazolyl] -ethyl)-tetrahydropyran-2-ol A total of 100 mg. of1-(3,5-dimethyl-4-isoxazolyl)-7- hydroxy-non-8-en-3-one was allowed toreact with 25 mg. of aluminum isopropoxide and 0.1 ml. of diethylaminein 5 ml. of refluxing toluene for one and one-half hours under anitrogen atmosphere. After cooling, the reaction mixture waschromatographed on 5 g. of silica gel using benzene-diethylamine (99:1)and (19:1) mixtures as eluants. A total of 127.8 mg. of product as anoil was obtained upon evaporation of the first 6 X 5 ml. fractions. Thismaterial was rechromatographed on 3.6 g. of alumina (activity 111).Elution with benzene and benzene containing 2 percent of diethylamine(total of 6 X 4 ml.) gave pure product2-(diethylamino)-6-(2-[3,5-dimethyl-4-isoxazolyl]-ethyl)-tetrahydropyran-2-olas an oil after evaporation of the solvents in vacuo. A total of mg. ofdesired product I was obtained in this fashion. The ir spectrum of thismaterial exhibited typical bands at 1640 cm (isoxazole moiety), 1,710 cm(carbonyl) and 3,400 (bonded OH). The compound had a uv maximum (inethanol) at 220 mu, e=5,350.

Elution of the column with more benzene-diethylamine afforded theconsiderably more polar isomeric S-hydroxy compound. When this materialwas refluxed for three hours with aluminum isopropoxide indiethylamine-benzene a mixture of the desired 2-hydroxy and S-hydroxycompounds in the respective ratio of about 2:1 was obtained. Thismixture may be separated by using the chromatographic procedure above.

EXAMPLE 6 Preparation of 2S,6R-[2-(S-a-phenethylamino)ethyl]-6-[ 2- (3,5-dimethyl-4-isoxazolyl)ethyl]-tetrahydropyran-2-ol A total of 1.25 g. ofl-(3,5-dimethyl-4-isoxazolyl)-7- hydroxy-non-B-en-S-one was reacted with300 mg. of aluminum isopropoxide and 908 mg. of ()-phenethylamine in 36ml. of refluxing toluene for 1 hour under a nitrogen atmosphere. Thereaction mixture was washed first with water and then with 3Nhydrochloric acid (3 X 20 ml.). The acid extract was washed twice withbenzene and then treated with ION sodium hydroxide and ice to bring thepH to about 1 1. Extraction with 3 X 50 ml. of benzene, washing withbrine, drying over sodium sulfate, followed by filtration andevaporation to dryness afforded 1.50 g. of crude product as an oil. Thismaterial was chromatographed on 75 g. of alumina (Activity lll). Elutionwith benzene (75 ml. fractions) gave, after The pure material (518 mg.)was resolved by crystallization from isopropyl ether to affordopticallypure (1 ,diastereoisomer) 2S,6R-2-[2-(S-a-phenethylamino)ethyl]-6-[where R R and R, are selected from the group consisting of hydrogen andlower alkyl; R, is selected from the group consisting of hydrogen, loweralkyl, lower alkyl phenyl and phenyl lower alkyl; R taken independentlyis hydrogen or lower alkyl; R taken independently is lower alkyl orphenyl lower alkyl; and R and R taken together with the adjacentnitrogen atom form a 5 or 6 membered saturated heterocyclic ringincluding at the most one additional hetero atom selected from the groupconsisting of nitrogen and oxygen wherein said hetero atom is not inadjacent position to said nitrogen atom which process comprises reactinga compound of the formula R i R R i W 7 R R3 R1 where R,, R R and R, areas above with an amine of the formula Nl-lR R where R and R are as abovein the presence of a metal alkoxide selected from the group consistingof sodium and aluminum lower alkoxides in an inert organic solvent at atemperature in the range of from about C. to the reflux temperature ofthe reaction medium.

2. The process of claim 1 wherein R and R are both hydrogen and R and Rare both methyl.

3. The process of claim 1 wherein said metal alkoxide is aluminumisopropoxide. v

4. The process of claim 3 wherein R, and R both are lower alkyl.

5. The process of claim 4 wherein R and R both are ethyl.

6. The process of claim 3 wherein NHR R is an optically active amine.

7. The process of claim 6 wherein said optically active where R R and R,are selected from the group consisting of hydrogen and lower alkyl; R,is selected from the group consisting of hydrogen, lower alkyl, loweralkyl phenyl and phenyl lower alkyl; R, taken independently ishydrogen-or lower alkyl; and R and R taken together with the adjacentnitrogen atom form a 5 or 6 membered saturated heterocyclic ringincluding at the most one ad ditional hetero atom selected from thegroup consisting of nitrogen and oxygen wherein said hetero atom is notin adjacent position to said nitrogen atom which process comprises incombination A. reacting a compound of the formula K OH where R and R,are as above and R and R are defined as R; and R respectively bothindependently and when taken together with a compound of the formulaElli --R Ri HO H112 O Hg J III where R,, R R and R are as above;

B. reacting the product from step A. above with hydroxylamine or a saltthereof so as' to obtain a compound of ths r V R4 I OH R R 1101M a 1where R R R and R are as above; C. cyclizing the product obtained fromstep B. above by heating in an organic solvent having a boiling pointabove 5Q- 2Q0bL C. so as to obtain a product of the formula Ra R1 whereR,, R R and R are as above; and E. reacting the product obtained fromstep D. above with an amine of the formula HNR R where R and R, are asabove in the presence of a metal alkoxide selected from the groupconsisting of sodium and aluminum lower alkoxides in an inert organicsolvent at a temperature in the range of from about 0 C. to the refluxtemperature of the reaction medium.

9. The process of claim 8 wherein R and R both are hydrogen, R and Rboth are methyl and R and R both are I ethyl.

10. The process of claim 8 wherein HNR R is an optically active amineand the product of formula I is obtained as a diastereoisomeric mixture.

11. A process for the preparation of compounds of the fol lowingformula:

wherein R,, R and R are selected from the group consisting of hydrogenand lower alkyl; R,, is selected from the group consisting of hydrogen,lower alkyl, lower alkylphenyl and phe'nyl lower alkyl; R, takenindependently is lower alkyl or phenyl lower alkyl; R, takenindependently is lower alkyl or hydrogen and R, and R, taken togetherwith the adjacent nitrogen atom form a 5 or 6 membered saturatedheterocyclic ring including at the most one additional hetero atomselected from the group consisting of nitrogen and oxygen wherein saidhetero atom is not in adjacent position to said nitrogen atom whichprocess comprises isomerizing in the presence of a metal alkoxideselected from the group consisting of sodium and aluminum loweralkoxides in an inert organic solvent at a temperature in the range offrom about 0 C. to the reflux temperature of the reaction medium acompound of the formula aluminum isopropoxide.

2. The process of claim 1 wherein R1 and R2 are both hydrogen and R3 andR4 are both methyl.
 3. The process of claim 1 wherein said metalalkoxide is aluminum isopropoxide.
 4. The process of claim 3 wherein R5and R6 both are lower alkyl.
 5. The process of claim 4 wherein R5 and R6both are ethyl.
 6. The process of claim 3 wherein NHR5R6 is an opticallyactive amine.
 7. The process of claim 6 wherein said optically activeamine is (-)-phenethylamine and the product of Formula I is obtained inthe form of a diastereoisomeric mixture which is resolved by fractionalcrystallization.
 8. The process for the preparation of compounds of thefollowing formula
 9. The process of claim 8 wherein R1 and R2 both arehydrogen, R3 and R4 both are methyl and R7 and R8 both are ethyl. 10.The process of claim 8 wherein HNR5R6 is an optically active amine andthe product of formula 1 is obtained as a diastereoisomeric mixture. 11.A process for the preparation of compounds of the following formula: 12.The process of claim 11 wherein said metal alkoxide is aluminumisopropoxide.